Identification and development of compounds capable of selectively targeting components of complex cell-signaling networks in a cell is a major effort of modern pharmacology. Cyclic adenosine monophosphate (cAMP), a prototypic second messenger, is an important component of cell-signaling networks that control numerous biological processes. In addition to its regulatory functions under physiological conditions, cAMP has been implicated in playing a major role in multiple human diseases, including cancer, diabetes, heart failure, and neurological disorders, such as Alzheimer's disease (AD). Therefore, it is not surprising that current pharmacological therapeutics target the cAMP signaling pathway more than any other pathway.
The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular cAMP receptor families: the classic protein kinase A/cAMP-dependent protein kinases (PKAs/cAPKs) and the more recently discovered exchange proteins directly activated by cAMP/cAMP regulated guanine nucleotide exchange factors (EPACs/cAMP-GEFs). While a number of pharmacological inhibitors of PKA are available, only a few EPAC specific antagonists/inhibitors have been described. Thus, there remains a need for additional compositions and methods for selectively modulating EPAC1 and/or EPAC2.